Heterocyclic compound

ABSTRACT

Endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1 -isopropyl-2(1H)-quinolone-3-carboxamide shown by formula (I): ##STR1## or an acid addition salt thereof exhibits a potent action for stimulating a serotonin 4 receptor and is effective for the treatment of diseases and for the improvement of conditions, caused by a reduced motility in the gastrointestinal tract.

This application is a 371 of PCT/JP 93/01484 filed Oct. 15, 1993.

TECHNICAL FIELD

The present invention relates to a heterocyclic compound. Moreparticularly, the present invention relates to a novel quinolonecompound, which has an action for stimulating a serotonin 4 receptor andis therefore useful for the treatment of chronic gastritis or forimproving digestive tract conditions accompanied by postoperativegastroparesis. The present invention also relates to a pharmaceuticaluse of such a quinolone compound.

BACKGROUND ART

Serotonin is a nurotransmitter which is widely distributed in human andhas a remarkable variety of physiological effects. It is hitherto knownthat a serotonin receptor includes three subtypes of serotonin 1receptor, serotonin 2 receptor and serotonin 3 receptor. In addition tothese receptors, it is reported by Dumuis, A., et al., MolecularPharmacology, 34, 880, 1988 that serotonin 4 receptor is existent.

Serotonin 4 receptor is considered to take a part in contraction of theileum or ascending colon of guinea pig or relaxation of rat esophagus.Cisapride and renzapride, which are stimulants of serotonin 4 receptor,accelerate gastrointestinal motor functions and improve gastrointestinalconditions such as chronic gastritis, heartburn accompanied bypostoperative gastroparesis, anorexia, bowel pain, abdominal distension,etc., and are thus considered to be effective for the treatment ofgastro-esophagal reflux, intestinal pseudo-obstruction and constipation[Alimentary Pharmacology and Therapeutics, 6, 273, 1992].

As heterocyclic compounds having an activity of antagonizing orstimulating serotonin receptors, European Patent No. 0458636A1 disclosesquinolone derivatives which exert on a serotonin 3 receptor antagonizingactivity.

On the other hand, U.S. Pat. No. 5,106,851 disclosesquinazoline-carboxylic acid derivatives as heterocyclic compoundseffective for the treatment of gastrointestinal disorders. However, thecompounds are merely known to show an affinity to muscarinic receptorsbut remain unknown about any action of serotonin receptors.

As stated above, no research has been reported on any heterocycliccompound having an excellent antagonizing or stimulating activityparticularly on serotonin 4 receptor.

Accordingly, the .object of the present invention is to provide a novelheterocyclic compound having a potent stimulating activity especially onserotonin 4 receptor and a pharmaceutical use thereof.

DISCLOSURE OF INVENTION

An object of the present invention is to provideendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamiderepresented by formula (I): ##STR2## as well as a pharmaceuticallyacceptable salt thereof.

Another object of the present invention is to provide a pharmaceuticalcomposition comprising as an effective ingredient the compound offormula (I) or its pharmaceutically acceptable salt and apharmaceutically acceptable carrier, particularly for stimulatingserotonin 4 receptor.

A further object of the present invention is to provide a method forstimulating serotonin 4 receptor which comprises administering to humanan effective dose of the compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

A still further object of the present invention is to provide thecompound of formula (I) or a pharmaceutically acceptable salt thereof,for use as an active ingredient of the pharmaceutical compositionparticularly for stimulating serotonin 4 receptor.

A still further object of the present invention is to provide use ofsaid compound or a salt thereof for the preparation of a pharmaceuticalcomposition comprising as an effective ingredient the compound offormula (I) or a pharmaceutically acceptable salt thereof and forstimulating serotonin 4 receptor.

BEST MODE FOR CARRYING OUT THE INVENTION

As the pharmaceutically acceptable salts of the compound of formula (I)in accordance with the present invention, there are acid addition salts.These acid addition salts are those obtained by adding pharmacologicallyacceptable acids to the nitrogen atom in the molecule of the compound offormula (I) and include salts of mineral acids such as hydrochloricacid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid orphosphoric acid; salts of organic acids such as acetic acid, oxalicacid, citric acid, tartaric acid, maleic acid, succinic acid, fumaricacid, p-toluenesulfonic acid, benzenesulfonic acid or methanesulfonicacid.

The compound of the present invention represented by formula (I)(hereinafter Compound (I)) can be produced, for example, by a processshown in the following production scheme. ##STR3##

Compound (2) used as the starting compound can be prepared by the methoddisclosed in J. Chem. Soc., 346, 1960.

For reductive ring closure from Compound (2) to Compound (3), reactionconditions for conventional reduction of a nitro group may be employed.The reduction and ring closure take place simultaneously to obtainCompound (3). Examples of reaction conditions for the reduction include:

(1) catalytic reduction in an appropriate solvent using palladium-carbonor platinum; and

(2) reduction in an appropriate inert solvent using iron or tin, orusing sodium sulfide-ammonium chloride.

The reduction in (1) above proceeds in a solvent and examples of thesolvent are water; acetic acid; an alcohol; a hydrocarbon such ashexane; an ether such as diethyl ether and tetrahydrofuran; a non-proticpolar solvent such as N,N-dimethylformamide; and a solvent mixturethereof. As a solvent employed in the reduction in (2) above, there arementioned, for example, water, acetic acid, methanol, ethanol anddioxane, and a solvent mixture thereof.

The reaction temperature for the reduction in the reactions (1) and (2)ranges generally from 0° C. to the boiling point of a solvent used; thereaction time is appropriately between 30 minutes and 12 hours.

Compound (3) is converted by N-isopropylation into Compound (4) underconventional conditions for N-alkylation of an acid amide. Morespecifically, N-isopropylation is carried out in an appropriate solventin the presence of a base, for example, a metal alkali such as sodiumand potassium; alkali hydride such as sodium hydride; an alkali alkoxidesuch as sodium ethoxide and potassium tertiary butoxide; an alkalihydroxide such as sodium hydroxide and potassium hydroxide; a carbonatesuch as sodium carbonate and potassium carbonate; an amine such astriethylamine and pyridine.

Examples of the solvent used for the N-isopropylation are an alcoholsuch as methanol and ethanol; an ether such as diethyl ether, dioxaneand tetrahydrofuran; a hydrocarbon such as hexane and benzene; anon-protic polar solvent such as N,N-dimethylformamide; or a solventmixture thereof. The reaction is performed generally at 0° C. up to theboiling point of a solvent used.

In general, the reaction time is appropriately set for 30 minutes to 12hours.

For introducing the isopropyl group into Compound (3), there is employeda reactive derivative such as an isopropyl halide, e.g., isopropyliodide.

Hydrolysis from Compound (4) to Compound (5) is performed underconventional conditions for hydrolysis, for example, acidic hydrolysisusing hydrochloric acid or acetic acid, alkaline hydrolysis using sodiumhydroxide. The reaction temperature is generally between 0° C. and theboiling point of a solvent used. In general, the reaction time isappropriately set in the range of 30 minutes to 12 hours.

Compound (5) is converted into Compound (1) by amidation of Compound (5)or its reactive derivative withendo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane (Compound (6)). ThusCompound (1) can be prepared.

The amidation may be carried out in a conventional manner.

For the amidation, there may be employed a method which comprisessuitably reacting a reactive derivative of Compound (5), e.g., its acidhalide, lower alkyl ester or activated ester, or its imidazolide ormixed anhydride with the aforesaid octane compound; or a method whichcomprises directly binding Compound (5) to Compound (6) using acondensing agent.

Where the acid halide is employed, the halide of Compound (5) is reactedwith Compound (6) generally in a solvent inert to the reaction at atemperature of from 0° C. to the boiling point of the solvent in thepresence of or absence of a base.

Examples of the solvent include ether, tetrahydrofuran, dioxane,methylene chloride, chloroform, dichloroethane, benzene, toluene,xylene, water or a mixture thereof.

Examples of the base which can be employed are potassium carbonate,sodium hydroxide, potassium hydroxide, pyridine, triethylamine andN,N-dimethylaniline.

In general, the reaction time is appropriately in the range of 30minutes to 12 hours.

Where the compounds are directly bound to each other using a condensingagent, Compound (5) is reacted with Compound (6) generally in a solventinert to the reaction at a temperature of from 0° C. to the boilingpoint of the solvent used in the presence of a condensing agent.

As the solvent, those mentioned above may be used in a similar manner.

Examples of the condensing agent which can be employed aredicyclohexylcarbodiimide, 2-chloro-N-methylpyridinum iodide anddiphenylphosphorylazide.

Compound (6) can be prepared by the method described in J. Am. Chem.Soc., 79, 4194, 1957.

Compound (4) or (5) in the reaction scheme described hereinabove mayalso be prepared by the process shown below: ##STR4##

Compound (8) can be prepared by oxidizing Compound (7) with an oxidizingagent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in asolvent such as dioxane.

Compound (8) may be converted into Compound (4) or (5) by condensingCompound (8) with malonic acid or a malonic acid ester in the presenceof or absence of a condensing agent.

Examples of the condensing agent which can be used include a hydroxide,carbonate, hydrogen carbonate, alcoholate and amide of an alkali metal;an amine such as ammonia and piperidine, acetic acid, acetic anhydrideand zinc chloride. The condensing agents may be used alone or inadmixture. Using Compound (4) or (5), the compound of the presentinvention can be prepared by the process as described above.

Toxicity of the compound represented by formula (1) which is theeffective ingredient of the pharmaceutical composition of the presentinvention was examined in terms of toxicity by mouse singleadministration (acute toxicity). The results indicate that the minimumlethal dose is more than 125 mg/kg by oral administration.

A dose of the compound represented by formula (1) which is the effectiveingredient of the pharmaceutical composition of the present inventionvaries depending upon condition. In general, a daily dose for adult isin the range of 0.1 to 100 mg/human for oral administration and 0.01 to20 mg/human for intravenous administration. The dose may be given atonce or by dividing the daily dose into 2 to 4 times.

The pharmaceutical composition of the present invention is prepared foruse into a solid preparation such as a tablet, a pill, a capsule orgranules, or into an injection, liquid, an emulsion or a suppository.

These pharmaceutical preparations may be made in a conventional mannerfor preparing medical compositions. If necessary and desired, anadditive which is conventionally used may be added to the preparations;examples of such an additive are an aid, a stabilizer, an emulsifier anda diluent.

Hereinafter the compound of formula (1) which is the effectiveingredient of the pharmaceutical composition of the present invention isspecifically described with respect to its serotonin 4 receptorstimulating activity, activity of stimulating various gastrointestinalmotor functions, and its toxicity.

Experiment 1. Serotonin 4 Receptor Stimulating Activity Compounds Tested

The compounds shown in the following Table 1 were examined.

                  TABLE 1                                                         ______________________________________                                         ##STR5##                                                                     Cpd. No.  R.sub.1   R.sub.2 R.sub.3                                           ______________________________________                                        Cpd. of the                                                                   invention                                                                     1         isopropyl H                                                                                      ##STR6##                                         Cpds. for                                                                     comparison                                                                    2         ethyl     H                                                                                      ##STR7##                                         3         n-propyl  H                                                                                      ##STR8##                                         4         n-butyl   H                                                                                      ##STR9##                                         5         isobutyl  H                                                                                      ##STR10##                                        6 Cpd. of USP 5,106,851                                                                 H         H                                                                                      ##STR11##                                        7 Cpd. of EP 0458636A1                                                                  n-butyl   OH                                                                                     ##STR12##                                        ______________________________________                                    

Method

Twitch responses were examined in longitudinal muscle strips of guineapig by a modification of the method described in The Journal ofPharmacology and Experimental Therapeutics, 252, 1378, 1990.

From Hartley guinea pigs, a section of ileum 25 cm in length andproximal to the ileocecal junction was removed. The longitudinal musclestrips obtained from two segments of ileum about 4 cm each in lengthwere used for this experiment. The longitudinal muscle strips weresuspended in Krebs' solution at 32° to 34° C. and bubbled with 95% O₂and 5% CO₂ under a load of about 0.8 g. Twitch responses were recordedunder electrical stimulation of 0.2 Hz, 1 msec pulse duration, usingforce displacement transducers. The longitudinal muscle strips,stimulated at supramaximal voltage, were allowed to equilibrate forabout an hour. After it was confirmed that the twitch responses wereenhanced by 10⁻⁸ M 5-hydroxytryptamine (5-HT), each agonist was examinedon its activity for twitch responses. The test was carried out byexposing the strips to cumulative additions of agonist at least at45-minute intervals.

Results

ED₅₀ of the serotonin 4 receptor stimulating activity is shown in Table2 below.

                  TABLE 2                                                         ______________________________________                                        Compound Tested     ED.sub.50 (nM)                                            ______________________________________                                        Compound of this invention                                                    1                   21.4                                                      Compound for Comparison                                                       2                   138                                                       3                   413                                                       4                   >3000                                                     5                   974                                                       6                   >3000                                                     7                   >3000                                                     ______________________________________                                    

As is appreciated from the results shown in Table 2, the compound of thepresent invention exhibited a much more potent serotonin 4 receptorstimulating activity than any of the other compounds having an alkylgroup other than isopropyl, i.e., Compounds 2 to 5 for comparison,Comparative Compound 6 recited in U.S. Pat. No. 5,106,851 andComparative Compound 7 recited in EP 0458636A1.

Experiment 2. Activity on Gastric Motility in Rat

Method:

Male Wistar rats weighing 250 to 350 g were fasted for 18 hours and thenprovided for experiment. The abdominal cavity was opened under etheranesthesia and a rubber balloon was inserted into the stomach via theforestomach. A cannula for administering a drug was put in theperitoneal cavity. After recovery from the anesthesia, the balloon wasconnected to low pressure transducers to record gastric motility in theconscious state.

The compound of the present invention was suspended in physiologicalsaline and the suspension was intraperitoneally administered.

Contraction frequency and motility index are shown in terms of aproportion (%) of a mean value calculated for 15 minutes to a valueprior to administration (0 minute). The value for 0 minute was made amean value for 30 minutes prior to the administration.

Results

The compound of the present invention accelerated the gastric motilityin a dose of 1 mg/kg, i.p. On the other hand, no affect was noted withthe vehicle alone.

Changes in contraction frequency and motility index caused byadministration of the compound of the present invention are shown inTable 3 below.

                  TABLE 3                                                         ______________________________________                                        Time after administration (minute)                                            0          10     20      30    40    50    60                                ______________________________________                                        Contraction                                                                           100    182.3  243.5*                                                                              187.0 134.7 134.9 141.6                           frequency                                                                     (%)                                                                           Motility                                                                              100    169.3  188.1 144.2 83.3  88.8  108.8                           index (%)                                                                     ______________________________________                                         *: P < 0.05, N = 4                                                       

Experiment 3. Activity on Gastrointestinal Motor in Dogs

The activity was determined by a modification of the method described inGastroenterologia Japonica, 12, 275, 1977.

Method

Beagle dogs of both sexes weighing 9 to 15 kg were anesthetized withsodium pentobarbital and strain gauge force transducers were sutured onfive (5) portions, i.e., for determining antral, duodenum, jejunal,ileal and colonal motor responses. A cannula for administering a drugwas mounted persistently into the jugular vein. After recovery of thesurgery, motor responses at those portions on the gastrointestinal tractin both during a fasting period and after feeding were determined in theconscious dogs.

The compound of the present invention was administered by dissolving thecompound in 5% lactate saline aqueous solution for intravenous injectionand for oral administration by suspending the compound in 5% gum arabicaqueous solution.

The motor index is shown in terms of a proportion (%) of a mean valuecalculated for 15 minutes to a value prior to administration (0 minute).The value for 0 minute was made a mean value for 30 minutes prior to theadministration. Results

The compound of the present invention showed acceleration on the motoraction of the gastrointestinal tract by intravenous and oraladministration, both during the fasting period and after feeding. On theother hand, no influence was noted when the vehicle alone was given.

Tables 4 and 5 below indicate the activity of the compound of thepresent invention in doses of 0.3 mg/kg intravenously and 1 mg/kgorally, respectively, on the gastric motor action after feeding.

                                      TABLE 4                                     __________________________________________________________________________    Intravenous Administration                                                    Time after administration (min)                                                     0  15 30 45  60  75  90  105 120                                        __________________________________________________________________________    Motility                                                                            100                                                                              371.4                                                                            322.6                                                                            282.3*                                                                            261.1*                                                                            281.9**                                                                           262.1*                                                                            242.9*                                                                            195.2                                      index (%)                                                                     __________________________________________________________________________     *: P < 0.05, **: P < 0.01, N = 3                                         

                                      TABLE 5                                     __________________________________________________________________________    Oral Administration                                                           Time after administration (min)                                                     0  15 30 45  60  75  90  105 120                                                                              180                                                                              210                                                                              240                               __________________________________________________________________________    Motility                                                                            100                                                                              116.4                                                                            193.5                                                                            191.4*                                                                            206.9**                                                                           202.2*                                                                            192.5*                                                                            207.3*                                                                            194.9                                                                            195.8                                                                            176.2                                                                            182.8                             index (%)                                                                     __________________________________________________________________________     *: P < 0.05, **: P < 0.01, N = 3                                         

Experiment 4. Activity on Gastric Emptying in Rat

The activity was investigated by a modification of the method describedin British Journal of Pharmacology, 91, 263, 1987.

Method

Male Wistar rats weighing 170 to 220 g were used which were deprived offood for 24 hours. Glass spheroids of 500 mg/ml were orally administeredto the animal in a dose of 1 ml 30 minutes after subcutaneousadministration or 60 minutes after oral administration, of drugs. Theglass spheroids remained in the stomach were recovered and their weightwas measured to determine gastric emptying to control motility.

The compound of the present invention was suspended in physiologicalsaline and the resulting suspension was administered.

Results

The compound of the present invention dose-dependently acceleratedgastric emptying in both oral and subcutaneous administration, as shownin Table 6 below.

                  TABLE 6                                                         ______________________________________                                        Route for                      Residual                                       administra-                                                                             Dose         No. of  rate in                                        tion      (mg/kg)      Case    stomach (%)                                    ______________________________________                                        p.o.      0.03         5       67.3                                                     0.3          5       64.5                                                     3.0          6       42.0                                           s.c.      0.1          5       51.8                                                     1.0          5       50.3                                                     10.0         4       36.8                                           ______________________________________                                    

Experiment 5. Activity on Intestinal Transit in Mice

The activity was determined by a modification of the method described inYAKURI-TO-CHIRYO, 10, 195, 1982.

Method

Male ICR mice weighing 20 to 30 g were used which were deprived of foodfor 24 hours. A suspension containing 5% carbon powder gum arabic wasorally administered to the animal in a dose of 1 ml 15 minutes aftersubcutaneous administration or 30 minutes after oral administration, ofdrugs. The intestinal tract was removed 20 minutes after. The entirelength of the intestinal tract and the distance of the carbon powdersmoved were measured, and a moving rate was calculated for controlanimal.

Results

The compound of the present invention accelerated the intestinal transitin both oral and subcutaneous administration, as shown in Table 7 below.

                  TABLE 7                                                         ______________________________________                                        Route for                                                                     administra-                                                                             Dose         No. of  Intestinal                                     tion      (mg/kg)      Case    transit (%)                                    ______________________________________                                        p.o.      1            5       100.6                                                    3            5       121.4                                                    10           6       120.4                                          s.c.      1            5       116.6                                                    3            4       117.8                                                    10           6       138.3**                                        ______________________________________                                         **: P < 0.01                                                             

Experiment 6. Toxicity on Consecutive 14-day Oral Administration in Rat

Toxicity of consecutive oral administration was investigated by oraladministration of male Wistar rats of 5 weeks age, weighing 124 to 140 gand seven rats forming one group, orally received the compound of thepresent invention for 14 consecutive days in a daily dose of 100 mg/kgor 250 mg/kg once a day. During the course of administration, generalconditions were observed and the body weight was measured. At the timewhen the administration was completed, hematological inspection,hematochemical inspection, urinalysis, anatomical finding, organ weightmeasurement and pathohistological inspection were performed. In the 250mg/kg group, prevention of body weight increase was noted and secondarychanges accompanied by aggravation of general conditions were observedin the liver, thymus, adrenogenital organ, adrenal, etc. However, notoxic change was noted in the 100 mg/kg group. Taking into account thepharmacological activities of the compound of the present invention, thetoxicity is reasonably assumed to be weak.

Hereinafter the present invention will be described below morespecifically, with reference to Preparation Examples and Examples.

PREPARATION EXAMPLE 1

Preparation ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide

1) Ethyl 2(1H)-quinolone-3-carboxylate

In 700 ml of acetic acid was dissolved 45 g of diethyl2-nitrobenzylidenemalonate (J. Org. chem., 3462, 1960). Whilemaintaining at 80° C., 53 g of iron powders were added by severalportions to the solution. The mixture was stirred for further 2 hours.

After the system was reverted to room temperature, the reaction mixturewas filtered through celite and the filtrate was concentrated in vacuo.The thus obtained oily substance was purified by silica gel columnchromatography (chloroform:methanol=10:1) to give 21.3 g of ethyl2(1H)-quinolone-3-carboxylate.

mp: 160°-163.2° C. (ethyl acetate)

2) Ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylate

After 20 g of ethyl 2(1H)-quinolone-3-carboxylate was added to asolution of 4.45 g of sodium hydride in 100 ml of DMF, 31.5 g ofisopropyl iodide was added to the mixture followed by stirring at 70° C.for 8 hours. After DMF was removed by distillation in vacuo, the residuewas poured into water. The mixture was then extracted with ethylacetate. After the organic layer was washed with water and then withsaturated sodium chloride aqueous solution, the organic layer was driedover anhydrous sodium sulfate.

The solvent was distilled off in vacuum. The resulting oily substancewas purified by silica gel column chromatography (ethylacetate:n-hexane=4:1) to obtain 1.55 g of ethyl1-isopropyl-2(1H)-quinolone-3-carboxylate.

mp: 54°-57° C. (ethyl acetate)

3) 1-Isopropyl-2(1H)-quinolone-3-carboxylic acid

A solution of 1.55 g of ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylateand 0.28 g of sodium hydroxide in a mixture of 10 ml of ethanol and 2 mlof water was stirred overnight at room temperature. After the solventwas distilled off, dil. hydrochloric acid was added to the residue. Theprecipitated solid was taken by filtration, washed with water and driedto give 1.22 g of 1-isopropyl-2(1H)-quinolone-3-carboxylic acid.

mp: 168°-169° C. (ethyl acetate)

4)Endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide

A solution of 0.5 g of 1-isopropyl-2(1H)-quinolone-3-carboxylic acid in5 ml of thionyl chloride was stirred for 2 hours at reflux. Afterthionyl chloride was completely distilled off in vacuo, 3 ml of benzenewas added to the residue. Under ice cooling, 3 ml of benzene containing0.36 g of endo-3-amino-8-methyl-8-azabicyclo[3.2.1]octane was dropwiseadded to the benzene solution of the acid chloride described above. Themixture was stirred for 2 hours at room temperature. After ethyl acetatewas added to the reaction mixture, the organic layer was washed withwater and then with saturated sodium bicarbonate aqueous solutionfollowed by drying over anhydrous magnesium sulfate. After the solventwas distilled off in vacuo, the residue was purified by alumina columnchromatography (chloroform) and recrystallized from ethyl acetate togive 0.39 g ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide.

mp: 175.8°-177.8° C. (ethyl acetate)

MS (m/z): 353(M⁺), 214, 172, 84

IR ν (cm⁻¹, KBr): 3263, 1673, 1528, 1206

NMR (ppm, CDCl₃): 1.68 (6H, d, J=7.2 Hz), 1.76 (1H, s), 1.83 (1H, s),2.00-2.40 (6H, m), 2.34 (3H, s), 3.10-3.28 (2H, m), 4.30 (1H, q, J=7.2Hz), 5.40-5.90 (1H, m), 7.22-7.33 (1H, m), 7.55-7.70 (2H, m), 7.75 (1H,d, J=7.8 Hz), 8.83 (1H, s), 10.48 (1H, d, J=7.2 Hz)

Elemental analysis for C₂₁ H₂₇ N₃ O₂ : Calcd. (%) C, 71.36; H, 7.70; N,11.88. Found (%) C, 71.21; H, 7.67; N, 11.84.

PREPARATION EXAMPLE 2

Preparation ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide

1) 2-Isopropylaminobenzyl alcohol

While maintaining at 0° to 5° C., 10 g of sodium borohydride was addedby several portions to a mixture of 10 g of 2-aminobenzyl alcohol, 13.3g of sodium acetate trihydrate, 40 ml of acetic acid, 80 ml of water, 30ml of ethanol and 30 ml of acetone. After stirring for an hour at thesame temperature, the reaction mixture was neutralized with sodiumhydrogen carbonate followed by extraction with ethyl acetate. Theorganic layer was washed with water and then with saturated sodiumchloride aqueous solution followed by drying over anhydrous magnesiumsulfate. After the solvent was distilled off in vacuo, the resultingoily substance was purified by silica gel column chromatography(hexane:ethyl acetate=2:1) and then distilled in vacuo to give 9.6 g of2-isopropylaminobenzyl alcohol.

bp: 110°-114° C. (4 m Hg)

2) 2-Isopropylaminobenzaldehyde

After 13.2 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) wasadded by several portions to a solution of 9.6 g of2-isopropylaminobenzyl alcohol in 200 ml of dioxane, the mixture wasstirred for further an hour. The solvent was removed by distillation toconcentrate the reaction mixture, and methylene chloride was then addedthereto followed by filtration. The filtrate was concentrated and theresulting oily substance was purified by silica gel columnchromatography (n-hexane:ethyl acetate=5:1) to obtain 7.6 g of2-isopropylaminobenzaldehyde.

NMR (ppm, CDCl₃): 1.27 (6H, d, J=6.4 Hz), 3.67-3.83 (1H, m), 6.59-6.73(2H, m), 7.31-7.43 (1H, m), 7.44 (1H, dd, J=7.6, 1.4 Hz), 8.26 (1H, s),9.79 (1H, s).

3) Ethyl 1-isopropyl-2(1H)-quinolone-3-carboxylate

A solution of 7.5 g of 2-isopropylaminobenzaldehyde, 11.0 g of diethylmalonate and 11.6 g of sodium hydrogen carbonate in 80 ml of aceticanhydride was stirred at 100° C. for 15 hours. After the solvent wasremoved by distillation in vacuo, water was added to the residue. Themixture was then extracted with ethyl acetate. After the organic layerwas washed with water and then with saturated sodium bicarbonate aqueoussolution, the organic layer was dried over anhydrous sodium sulfate. Thesolvent was distilled off in vacuum. The resulting oily substance waspurified by silica gel column chromatography (n-hexane:ethylacetate=4:1) to obtain 7.3 g of ethyl1-isopropyl-2(1H)-quinolone-3-carboxylate.

4)Endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide

The procedures were carried out in a manner similar to PreparationExamples 1-4) and 1-5) to giveendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide.

PREPARATION EXAMPLE 3

Preparation ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamidehydrochloride

In 3 ml of tetrahydrofuran was dissolved 100 mg ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide.The solution was acidified by adding an aqueous hydrochloric acid. Theprecipitated crystals were taken out by filtration and dried to give 107mg ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamidehydrochloride.

mp: 267°-270° C.

PREPARATION EXAMPLE 4

Preparation ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamidemaleate

In 3 ml of ethyl acetate was dissolved 100 mg ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamide.To the solution was added 3 mg of maleic acid. The precipitated crystalswere taken out by filtration and dried to give 106 mg ofendo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamidemaleate.

mp: 207°-210° C.

Pharmaceutical Composition

Tablet

Composition (Per Tablet)

    ______________________________________                                        Compound of this invention                                                                         2 mg                                                     Lactose             19 mg                                                     Potato starch       20 mg                                                     Crystalline cellulose                                                                             28 mg                                                     Carboxymethyl cellulose                                                                           20 mg                                                     Hydroxymethyl cellulose                                                                           10 mg                                                     Magnesium stearate   1 mg                                                     ______________________________________                                    

Method

After 20 g of the compound of this invention, 190 g of lactose, 20 g ofpotato starch, 280 g of crystalline cellulose, 200 g of carboxymethylcellulose and 100 g of hydroxymethyl cellulose were blended with eachother, the mixture was ground into powders with a crusher and thenstirred. The powders were put in a granulator and a small quantity ofwater was added to the powders for granulation. The granules were thendried with a fluid bed drier and 10 g of magnesium stearate was added tothe granules. The mixture was tableted with a tableting machine toobtain tablets each 100 mg in weight and 6 mm in diameter, containing 2mg of the compound of the present invention.

Industrial Applicability

The compound of the present invention acts on a serotonin 4 receptorthereby to exert on a serotonin-like receptor stimulating activity. Morespecifically, the compound of the present invention exhibits an actionof activating gastrointestinal motor functions to improvegastrointestinal conditions such as chronic gastritis, heartburnaccompanied by postoperative gastroparesis, anorexia, bowel pain,abdominal distension, etc., and are thus effective for the treatment ofgastro-esophagal reflux, intestinal pseudo-obstruction and constipation.

We claim: 1.Endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-1-isopropyl-2(1H)-quinolone-3-carboxamideor a pharmaceutically acceptable salt thereof.
 2. A pharmaceuticalcomposition comprising as an effective ingredient the compound accordingto claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 3. A pharmaceutical compositionaccording to claim 2, which is for stimulating a serotonin 4 receptor.4. A pharmaceutical composition according to claim 2, which is foractivating a gastrointestinal motor function.
 5. A method forstimulating a serotonin 4 receptor which comprises administering tohuman an effective dose of the compound or a pharmaceutically acceptablesalt thereof according to claim
 1. 6. A method according to claim 5,which is for activating a gastrointestinal motor function.
 7. A compoundor a pharmaceutically acceptable salt thereof according to claim 1, foruse as an effective ingredient of a pharmaceutical composition.
 8. Acompound or a pharmaceutically acceptable salt thereof according toclaim 7, wherein said pharmaceutical composition is a pharmaceuticalcomposition for stimulating a serotonin 4 receptor.
 9. A compound or apharmaceutically acceptable salt thereof according to claim 7, whereinsaid pharmaceutical composition is a pharmaceutical composition foractivating a gastrointestinal motor function.
 10. Use of a compound or apharmaceutically acceptable salt thereof according to claim 1, for thepreparation of a pharmaceutical composition comprising as an effectiveingredient said compound or a pharmaceutically acceptable salt thereofand for stimulating a serotonin 4 receptor.
 11. Use according to claim10, wherein said pharmaceutical composition is a pharmaceuticalcomposition for activating a gastrointestinal motor function.
 12. Apharmaceutical composition according to claim 3, which is for activatinga gastrointestinal motor function.
 13. A compound of a pharmaceuticallyacceptable salt thereof according to claim 8, wherein saidpharmaceutical composition is a pharmaceutical composition foractivating a gastrointestinal motor function.